{"doi":"10.1128/spectrum.01846-24","title":"Distinct impacts of each anti-anti-sigma factor ortholog of the chlamydial Rsb partner switching mechanism on development in <i>Chlamydia trachomatis</i>","abstract":"ABSTRACT Partner switching mechanisms (PSMs) are signal transduction systems comprised of a sensor phosphatase (RsbU), an anti-sigma factor (RsbW, kinase), an anti-anti-sigma factor (RsbV, the RsbW substrate), and a target sigma factor. Chlamydia spp. are obligate intracellular bacterial pathogens of animals that undergo a developmental cycle transitioning between the infectious elementary body (EB) and replicative reticulate body (RB) within a host cell-derived vacuole (inclusion). Secondary differentiation events (RB to EB) are transcriptionally regulated, in part, by the housekeeping sigma factor (σ 66 ) and two late-gene sigma factors (σ 54 and σ 28 ). Prior research supports that the PSM in Chlamydia trachomatis regulates availability of σ 66 . Pan-genome analysis revealed that PSM components are conserved across the phylum Chlamydiota, with Chlamydia spp. possessing an atypical arrangement of two anti-anti-sigma factors, RsbV1 and RsbV2. Bioinformatic analyses support RsbV2 as the homolog to the pan-genome-conserved RsbV with RsbV1 as an outlier. This, combined with in vitro data, indicates that RsbV1 and RsbV2 are structurally and biochemically distinct. Reduced levels or overexpression of RsbV1/RsbV2 did not significantly impact C. trachomatis growth or development. In contrast, overexpression of a non-phosphorylatable RsbV2 S55A mutant, but not overexpression of an RsbV1 S56A mutant, resulted in a 3 log reduction in infectious EB production without reduction in genomic DNA (total bacteria) or inclusion size, suggesting a block in secondary differentiation. The block was corroborated by reduced production of σ 54/28 -regulated late proteins and via transmission electron microscopy. IMPORTANCE Chlamydia trachomatis is the leading cause of reportable bacterial sexually transmitted infections (STIs) and causes the eye infection trachoma, a neglected tropical disease. Broad-spectrum antibiotics used for treatment can lead to microbiome dysbiosis and increased antibiotic resistance development in other bacteria, and treatment failure for chlamydial STIs is a recognized clinical problem. Here, we show that disruption of a partner switching mechanism (PSM) significantly reduces infectious progeny production via blockage of reticulate body to elementary body differentiation. We also reveal a novel PSM expansion largely restricted to the species infecting animals, suggesting a role in pathogen evolution. Collectively, our results highlight the chlamydial PSM as a key regulator of development that could be a potential target for novel therapeutics.","journal":"Microbiology Spectrum","year":2024,"id":505484,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9672,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1331032,"name":"Vandana Singh","orcid":"0000-0002-8243-1343","position":1,"is_corresponding":false},{"id":1356411,"name":"Aamal Ghazi Mahdi Al-Saadi","orcid":"0000-0002-9501-221X","position":2,"is_corresponding":false},{"id":893042,"name":"Nicholas Wood","orcid":"0000-0003-2527-5441","position":3,"is_corresponding":false},{"id":421814,"name":"Scott D. Hamilton-Brehm","orcid":"0000-0002-7474-207X","position":4,"is_corresponding":false},{"id":326294,"name":"Scot P. Ouellette","orcid":"0000-0002-3721-6839","position":5,"is_corresponding":false},{"id":526671,"name":"Derek J. Fisher","orcid":"0000-0002-1663-8389","position":6,"is_corresponding":false},{"id":1356703,"name":"Shiomi Junker","orcid":null,"position":0,"is_corresponding":true}],"reference_count":71,"raw_metadata":null,"created_at":"2026-07-19T02:10:47.170978Z","pmid":"39470281","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}